Adaptation to chronic mTOR inhibition in cancer and in aging

Abstract

The mTOR [mammalian (or mechanistic) target of rapamycin] protein kinase co-ordinates catabolic and anabolic processes in response to growth factors and nutrients and is a validated anticancer drug target. Rapamycin and related allosteric inhibitors of mTORC1 (mTOR complex 1) have had some success in specific tumour types, but have not exhibited broad anticancer activity, prompting the development of new ATP-competitive mTOR kinase inhibitors that inhibit both mTORC1 and mTORC2. In common with other targeted kinase inhibitors, tumours are likely to adapt and acquire resistance to mTOR inhibitors. In the present article, we review studies that describe how tumour cells adapt to become resistant to mTOR inhibitors. mTOR is a central signalling hub which responds to an array of signalling inputs and activates a range of downstream effector pathways. Understanding how this signalling network is remodelled and which pathways are invoked to sustain survival and proliferation in the presence of mTOR inhibitors can provide new insights into the importance of the various mTOR effector pathways and may suggest targets for intervention to combine with mTOR inhibitors. Finally, since chronic mTOR inhibition by rapamycin can increase lifespan and healthspan in nematodes, fruitflies and mice, we contrast these studies with tumour cell responses to mTOR inhibition.

Combined therapy with RAD001 e BEZ235 overcomes resistance of PET immortalized cell lines to mTOR inhibition

“…The sensitivity to rapalogs has been associated to low eIF4E/4EBP1 ratios, whereas increased eIF4E expression and/or decreased 4EBP1 expression confer resistance in cancer cells [30]. However, we found that the eIF4E/4EBP1 ratio was not significantly different in RAD001-sensitive (BON-1) and insensitive (QGP-1 and BON-1 RR) PET cells (Supplementary Figure 6), suggesting that another mechanism is involved.…”

“…Adaptation of cancer cells to chronic treatment with rapalogs has been attributed to feedback activation of the PI3K/AKT pathway and to the consequent induction of prosurvival responses in cancer cells [17, 30]. Moreover, for unknown reasons rapalogs efficiently block mTORC1-dependent S6 kinase activation but poorly suppress mTORC1-dependent phosphorylation of 4EBPs [30].…”

“…Moreover, for unknown reasons rapalogs efficiently block mTORC1-dependent S6 kinase activation but poorly suppress mTORC1-dependent phosphorylation of 4EBPs [30]. This weakness can be, however, overcome by new generation mTOR inhibitors that directly target the catalytic activity of the kinase [31, 32].…”

“…Thus, our results suggest that targeting the mTORC1 complex with allosteric and catalytic inhibitors synergistically impairs PET cell proliferation. In this regard, BEZ235 may present several advantages with respect to other catalytic inhibitors of mTOR [30, 35], because the clinical use of BEZ235 is already in a more advanced stage (see below) and this drug can concomitantly inhibit the PI3K pathway, thus possibly reinforcing growth inhibition.…”

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

“…Cancer cells have adapted to mTOR inhibition by downregulating the expression and translation of 4E-BPs [96]. Increases in the eIF4E-4E-BP1 ratio, limits the effect of mTOR inhibitors [69].…”